Abstract Inflammatory bowel disease (IBD) is caused by an inappropriate immune response, typically against intestinal microbes, resulting in inflammation of the intestines. In the last five years alone, 70,000 new IBD cases have been diagnosed in the US, representing a serious public health challenge of increasing medical and socio? economic importance. IBD is triggered by environmental factors, which within the intestine, is rich in microbes - beneficial, commensal as well as pathogenic. Here we will study the interactions between a beneficial bacteria Bacillus subtilis and an opportunistic fungal pathogen Candida albicans. Overgrowth of C. albicans in the gut has been linked to inflammation of the digestive tract. Some associated genetic and environmental factors have been characterized but the underlying molecular and immunological mechanisms remain unknown. This proposal will test the role of microbial interactions and associated immune responses. Microbes residing in the host niche of the gut must cope with alterations during long-term persistence in the host. They must also adapt rapidly to changes to ensure growth and survival during infection. Our goal is to determine the molecular mechanisms of cross-kingdom microbial interaction and host-microbe interactions with in a live host to gain a better understanding of healthy interactions versus disease. Our working hypothesis is that B. subtilis has probiotic properties because pre-exposure to B. subtilis protects the host from future C. albicans infections. We are just beginning to understand the genes involved in the interaction between C. albicans and B. subtilis as well as C. albicans and the host. Here, we will identify the molecular mechanisms that govern disease progression, and determine how specific mutations directly affect microbial interactions, host recognition, host response, and virulence. One of the major virulence factors in C. albicans is its morphogenic plasticity. We will use multiple morphogenic forms of C. albicans ? pathogenic forms as well as GUT-adapted commensals forms that are able to evade the host innate immune system thereby affecting disease outcomes. We will also use B. subtilis mutants that are unable to form protective biofilms and strains where key proteins are fluorescently tagged for microscopy. These investigations will be conducted in the intestine of a live animal host ? C. elegans. We will address the following questions: (1) what bacterial genes dictate the outcome of a fungal infection? (2) how fit are these mutants under physiologically relevant infection conditions within a live host? (3) what host innate immunity genes are involved in maintaining a healthy microbiota? (4) how does the host recognize and respond to the repertoire of morphologies it encounters? These studies will advance our understanding of microbial interactions from the pathogen perspective and will help reveal the role of the host in maintaining balanced relationship in healthy individuals as well as how disruption of this interaction causes devastating inflammation in the host.